Gene Validity Classification Summary

Gene/Disease Pair:

CPS1 : carbamoyl phosphate synthetase I deficiency disease

HGNC:2323 | MONDO_0009376
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 12
11.85
12
Funghini S et al. 2012 Feb 10 (PMID:22173106); Klaus V et al. 2009 Sep (PMID:19793055); Häberle J et al. 2003 Apr (PMID:12655559); Wakutani Y et al. 2004 (PMID:15617192); Yamaguchi M et al. 2016 Jun (PMID:27150549); Choi R et al. 2017 Jan (PMID:27834067);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
2
Funghini S et al. 2012 Feb 10 (PMID:22173106); Hoshide R et al. 1993 May (PMID:8486760); Häberle J et al. 2003 Apr (PMID:12655559); Finckh U et al. 1998 (PMID:9711878);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 2
3
2
Jackson MJ et al. 1986 (PMID:3545062);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Khoja S et al. 2018 Aug (PMID:29801986); Schofield JP et al. 1999 Jan (PMID:9862865);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Khoja S et al. 2018 Aug (PMID:29801986);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
10/12/2018
EXPERT CURATION (DATE)
Definitive
10/12/2018
EVIDENCE SUMMARY
The relationship between CPS1 and carbamoyl phosphate synthetase 1 deficiency (autosomal recessive inheritance) was evaluated using the ClinGen Clinical Validity Framework as of October 10th, 2018. Variants in CPS1 were first reported in humans with this disease as early as 1993 (Roshide et al., PMID 8486760). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in more than 20 probands in 8 publications (Hoshide et al, 1993, PMID 8486760; Haberle et al, 2003, PMID 12655559; Wakutani et al, 2004, PMID 15617192; Eeds et al, 2006, PMID 16737834; Klaus et al, 2009, PMID 19793055; Funghini et al, 2012, PMID 22173106; Yamaguchi et al, 2016, PMID 27150549; Choi et al, 2017, PMID 27834067). More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 points) has been reached. The mechanism for the disease is loss of function. This gene-disease association is supported by the biochemical function of carbamoyl phosphate synthetase (which catalyzes the first step of the urea cycle) (Jackson et al, 1986, PMID 3545062), knock out and conditional knockout mouse models (Schofield et al, 1999, PMID 9862865; Khoja et al, 2018, PMID 29801986), and gene therapy rescue in mouse models (Khoja et al, 2018, PMID 29801986). In summary, CPS1 is definitively associated with autosomal recessive carbamoyl phosphate synthetase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.